1. Field of the Invention
The present invention relates to nanocomposite particles. More particularly, the present invention provides a method for synthesizing stable, well dispersed, unagglomerated core/shell nanocomposite particles of varying sizes that may be used for a wide variety of applications.
2. Description of Related Art
One of the most important developments in the field of chemical technologies is that of nanostructuring. Nanostructured materials are assemblies of nano-sized units that display unique, characteristic properties at a macroscopic scale. The size range of such units lies within the colloidal range, where the individual properties are different to both those of atoms/molecules and to those of the bulk. The properties of the nanostructured assemblies, therefore, can be tuned by varying the colloidal properties of the constituents, mainly particle size, surface properties, interparticle interactions and interparticle distance.
The use of nanoparticles in biomedical applications is a major focus of numerous research groups today. Nanoparticles possess several qualities that make them useful in biomedical applications, such as diagnostic bioimaging, drug delivery, and gene therapy. Nanoparticles also can be used as bioimaging agents to label cells in cultures, tissues, or intact organisms.
Current nanoparticle technologies used in bioimaging applications include magnetic nanoparticles, ferrofluids, and quantum dots (QDs). Recently, there have been numerous advances in the development of colloidal fluorescent semiconductor nanocrystals, a class of QDs used for biological labeling (marketed as Q-dots™), such as ZnS shell-CdSe core nanoparticles. (Haugland, R. P. Molecular Probe, 6:320-328, 1998). Researchers are in the process of developing bioconjugation schemes and applying such probes to biological assays, and nanocrystals can be of particular benefit as biological labels when compared to existing organic dyes. Quantum dots have been widely tested in a range of bioimaging applications.
Semiconductor nanocrystals have several problems associated with their use, such as solubility, physicochemical stability and quantum efficiency of the semiconductor nanocrystals. Additionally, QD emissions are strongly intermittent and agglomeration can limit their effectiveness as a bioimaging tool. Other problems associated with QDs include surface electronic defects and toxicological effects, as surface oxidation can cause degradation of the QD shell, releasing toxic metals into the body, and poor crystallinity, which makes the interpretation of the physical properties of QDs very difficult. Furthermore, the routine application of fluorescent nanoparticles as biolabels is controversial, particularly because of general environmental concerns regarding the use of highly toxic compounds, such as cadmium, in biomedical diagnostics. Moreover, methods for designing nanometer-sized structures and controlling their shape to yield new materials with novel electronic, optical, magnetic, transport, photochemical, electrochemical and mechanical properties are rarely found and present a potentially rewarding challenge.
Nanoparticles also can function as a mechanism for drug delivery, which permits the utilization of numerous water-insoluble and unstable drugs. Additionally, nanoparticles can find use in drug targeting and extended release applications based on resorbable shell technologies. In addition, nanocomposites can be used in gene therapy for the delivery of genetic materials. Current nanoparticle drug and gene “carriers” include polymeric micelles, liposomes, low-density lipoproteins, polymeric nanospheres, dendrimers, and hydrophilic drug-polymer complexes.
Over the past ten years, extensive research has been carried out in the field of fabrication of nanoscale composite particles because of their unique properties and potential applications in electronics and photonics. Silicon dioxide (SiO2)-shell metallic-core structured nanocomposite particles were first synthesized and reported by Mulvaney et al. (Langmuir, 12:4329-4335, 1996), and by Adair et al. (Materials Sci. & Eng. R., 23:139-242, 1998). Most of the SiO2 coated nanocomposite particles having a core-shell architecture fall into two categories based on the synthetic method used. The approach developed by Mulvaney et al. involved the modification of metal cluster surfaces with the silane-coupling agent 3-aminopropyltriethoxysilane (APS) before the formation of the silica shell. APS is used as an adhesion promoter between the vitreophobic metal cluster core and the SiO2. The state of dispersion for the nanocomposites in suspension, however, was not examined by Mulvaney et al. or Adair et al. Adair et al. were successful in coating metallic and CdS clusters with SiO2 via simple hydrolysis and condensation of tetrethoxysilane (TEOS) in a cyclohexane/Igepal/water tertiary system having an aqueous phase. This system allows for a very uniform silica-shell coating along with a tunable thickness of both the core and the shell due to the confining of water droplets in oil.
Major limitations in the use of nanoparticles in therapeutic agent delivery applications involve the lack of colloidal stability in nanoparticle suspensions, agglomeration, polydispersity in size and shape, swelling, and leakage. Other problems include difficulty of synthesis and processing techniques, inadequate loading inside the carrier particle, and lack of applicability to a variety of medical agents. Residual precursor materials present in unwashed nanosuspensions can also have detrimental effects for both targeted delivery and toxic effects on the physiological system. In a typical chemical synthetic method, dispersion of nanoparticles essentially begins with the washing of the freshly prepared nanoparticles. However, washing and dispersion of nanoparticles is a challenge because of the strong van der Waals attraction between adjacent nanoparticles. For this reason, nanoparticle suspensions usually are stabilized with surface coatings of surfactant, which effectively balances the interaction forces with a high repulsion potential created by the surfactant molecules. It is necessary, however, to minimize the surfactant dispersants in order to achieve better performance for nanoparticle-based applications and devices. This is because surfactant additives are transferred to the subsequent process steps and can negatively impact the homogeneity of the arrays assembled from the nanoparticles. Furthermore, when protective surfactants are removed with conventional washing techniques, such as centrifugation, the nanoparticles tend to undergo agglomeration. The presence of agglomerates also can compromise the effective yield of particles. If nanometer-size primary particles are desired, the presence of agglomerates that are generally an order of magnitude or larger in size must be avoided. For example, prior art conventional methods for fabricating nanocomposite particles, such as filtration methods, as disclosed in U.S. Pat. No. 6,548,264, 2003 to Tan, W. et al., and discussed in more detail below, result in nanocomposite particles that are irreversibly agglomerated with an agglomeration size of about 250 nm.
Considering the current limitations in nanomedicine, there is a need for a universally applicable nanoparticle with controlled time-release, high loading of therapeutic agent(s), ease of preparation, stability, and up-scaling capabilities. The formulation of a stable, non-aggregating colloid to deliver active-medical-agents has the potential to transform the medical field by providing universal, controlled, targeted, systemic delivery for a variety of bioimaging and therapeutic agents.